Nikkomycin derivatives

ABSTRACT

Nikkomycin derivatives have been found to be orally or parenterally effective as anti-fungals in animals. They may be used alone or, preferably, in combination with azole antimycotics for a synergistic anti-fungal effect.

This application is a division of application Ser. No. 161,645, filedFeb. 29, 1988, now U.S. Pat. No. 4,914,087.

Related Application: U.S. Ser. No. 07/118,078, filed Nov. 9, 1988 by thesame applicants and entitled "Antimycotic Compositions of NikkomycinCompounds and Azole Antimycotics".

BACKGROUND OF THE INVENTION

1. Field

The invention is related to nikkomycin derivatives, antimycoticcompositions containing nikkomycin derivatives, antimycotic compositionscomprising fungicidally effective amounts of a nikkomycin derivative andan azole antimycotic, the preparation of such compositions and themethods of treating infections of fungi by administering therapeuticallyeffective amounts of such compositions.

2. Prior Art

Compounds inhibitory to the synthesis of fungal cell wall material(synthase inhibitors) have been reported recently to have demonstrableeffects against fungi of agricultural importance (U.S. Pat. Nos.4,315,922 and 4,158,608; see also U.S. Pat. Nos. 4,585,761 and 4,552,954for descriptions of the preparation and purification of such compounds).The agents mentioned in the cited patents, nikkomycins, together withsimilar agents known as polyoxins, are known to act by interfering withthe synthesis of chitin in the cell walls of fungi. Because fungi ofmedical importance to humans also have varying amounts of chitin intheir cell walls, experiments have been conducted to determine if thechitin synthase inhibitors are capable of inhibiting the growth of suchfungi (Hector and Pappagianis, J. Bacteriol. 154:488-498, 1983, andHector and Braun, Antimicrobial Agents Chemother, 29:389-394, (1986). Inearlier work, certain fungi such as Candida albicans were reported to beinsensitive to chitin synthase inhibitors (see Naider et al,Antimicrobial Agents Chemother, 24:787 796, 1983). Subsequently, C.albicans was found to be more sensitive to nikkomycins than polyoxins(see Yadan et al, J. Bacteriol. 160:884-888, 1984).

Quite surprisingly, it was now found that nikkomycin derivatives incombination with antimycotically active azoles are efficacious intreating fungal infections in human and non-human animals, especially byparenteral but also oral application and administration.

As shown in synergy studies the achieved antifungal effect is also asynergistic effect based on combining the nikkomycin derivatives withantimycotic azoles.

Accordingly, the invention is related to new nikkomycin derivatives andantimycotic compositions comprising a fungicidally effective amount of anikkomycin derivative and an azole antimycotic.

The nikkomycin derivatives of the invention are represented by thegeneral formulae (N) ##STR1## wherein R_(n) represents ##STR2## a) R_(w)denotes H or --CH₂ --X, wherein X is H, alkyl, preferably C₁ -C₆ -alkyl,aryl, preferably C₆ -C₁₈ -aryl, aralkyl, preferably C₆ -C₁₂ -aryl-C₁ -C₆-alkyl or any other saturated or unsaturated organic radical and R_(y)denotes --Ch₂ --X, wherein X has the aforementioned meaning;

b) R_(w) denotes H and R_(y) denotes ##STR3## wherein X' is anysaturated or unsaturated organic radical, especially a radical derivedfrom a natural amino acid;

c) R_(w) denotes H and R_(y) denotes a radical ##STR4## wherein X hasthe meaning mentioned under a) and b) hereinbefore and wherein X' hasthe meaning of the natural amino acids Gly, Val, Leu, Ile, Ser, Asp,Asn, Glu, His, Gys, Met and Phe or ##STR5## d) R_(w) denotes H and R_(y)has the meaning of ##STR6## wherein a') R_(n') denotes H or --CH₂ --Xand R_(v') denotes --CH₂ --X, wherein X has the meaning mentioned undera) hereinabove;

b') R_(n') represents H and R_(v') means ##STR7## wherein X' has themeaning mentioned under b) hereinabove; c') R_(n') denotes H and R_(v')represents ##STR8## wherein X and X' have the meaning given under a) andb) hereinabove or ##STR9## wherein R_(n) represents ##STR10## a) R_(w)denotes H or --CH₂ --X, wherein X is H, alkyl, preferably C₁ -C₆ -alkyl,aryl, preferably C₆ -C₁₈ -aryl, aralkyl, preferably C₆ -C₁₂ -aryl-C₁ -C₆-alkyl or any other saturated or unsaturated organic radical and R_(y)denotes --CH₂ --X, wherein X has the aforementioned meaning;

b) R_(w) denotes H and R_(y) denotes ##STR11## wherein X' is anysaturated or unsaturated organic radical, especially a radical derivedfrom a natural amino acid;

c) R_(w) denotes H and R_(y) denotes a radical ##STR12## wherein X andX' have the meaning mentioned under a) and b) hereinbefore with theproviso that X' has not the meaning ##STR13## d) R_(w) denotes H andR_(y) has the meaning of ##STR14## wherein a') R_(n') denotes H or --CH₂--X and R_(v') denotes --CH₂ --X, wherein X has the meaning mentionedunder a) hereinabove;

b') R_(n') represents H and R_(v') means ##STR15## wherein X' has themeaning mentioned under b) hereinabove; c') R_(n') denotes H and R_(v')represents ##STR16## wherein X and X' have the meaning given under a)and b) hereinabove or ##STR17## wherein R_(n) represents ##STR18## a)R_(w) denotes H or --CH₂ --X, wherein X is H, alkyl, preferably C₁ -C₆-alkyl, aryl, preferably C₆ -C₁₈ -aryl, aralkyl, preferably C₆ -C₁₂-aryl-C₁ -C₆ -alkyl or any other saturated or unsaturated organicradical and R_(y) denotes --CH₂ --X, wherein X has the aforementionedmeaning;

b) R_(w) denotes H and R_(y) denotes ##STR19## wherein X' is anysaturated or unsaturated organic radical, especially a radical derivedfrom a natural amino acid;

c) R_(w) denotes H and R_(y) denotes a radical ##STR20## wherein X andX' have the meaning mentioned under a) and b) hereinbefore; d) R_(w)denotes H and R_(y) has the meaning of ##STR21## wherein a') R_(n') andR_(v') denote H;

b') R_(n') denotes H or --CH₂ --X and R_(v') denotes --CH₂ --X, whereinX has the meaning mentioned under a) hereinabove;

c') R_(n') represents H and R_(v') means ##STR22## wherein X' has themeaning mentioned under b) hereinabove; d') R_(n') denotes H and R_(v')represents ##STR23## wherein X and X' have the meaning given under a)and b) hereinabove. If X' is an organic radical than preferably asaturated or unsaturated aliphatic radical, such as C₁ -C₁₀ -alkyl,alkenyl or alkinyl or a substituted or unsubstituted aromatic radicalwith 6 to 12 C-atoms or a heterocyclic radical, especially of the groupconsisting of ##STR24##

A preferred object of the present invention are antimycotic compositionscontaining nikkomycin derivatives and azole antimycotics morespecifically described in GB-PS 1,351,542, CA-PS 225,504, CA-AS 946,391,AU-PS 542,110, AU-PS 551,411, US-PS 4,301,166, US-PS 4,381,306, US-PS4,246,274, US-PS 4,238,498, US-PS 4,207,328, US-PS 3,986,229 and DE-OS3,242,249 which are incorporated into this patent application byreference.

Another preferred embodiment of the present invention are antimycoticcompositions containing nikkomycin derivatives and azole antimycoticsdescribed in the following paragraphs.

a) Diazolylalkyl-carbinols of the general formula ##STR25## in which Arepresents a nitrogen atom or the CH group,

B represents a nitrogen atom or the CH group,

X represents a hydrogen or alkyl,

Y represents alkyl, or alkenyl, alkinyl or optionally substitutedbenzyl, if X represents hydrogen, and

R represents optionally substituted phenyl or the grouping ##STR26##wherein Alk¹ represents alkyl and

Alk² represents alkyl, or

Alk¹ and Alk² together represent a cycloaliphatic ring, and

R¹ represents alkyl, alkenyl or in each case optionally substitutedphenyl, phenylalkyl, phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl,benzyloxy or benzylthio,

and physiologically acceptable acid addition salts thereof.

The compounds of the formula (I) sometimes have two asymmetric carbonatoms. In this case, they can exist in two geometric isomer forms.

The substituted diazolylalkyl-carbinols of the formula (I) are obtainedby a process in which azolyloxiranes of the formula ##STR27## in whichB, R, X and Y have the abovementioned meaning, are reacted with azolesof the formula ##STR28## in which A has the abovementioned meaning, inthe presence of a diluent and, if appropriate, in the presence of abase.

Preferably, in formula (I)

A represents a nitrogen atom or the CH group,

B represents a nitrogen atom or the CH group,

X represents hydrogen or straight-chain or branched alkyl with 1 to 6carbon atoms,

Y represents straight-chain or branched alkyl with 1 to 6 carbon atoms;or, if X represents hydrogen, also straight-chain or branched alkenyl oralkinyl with in each case 3 to 6 carbon atoms or benzyl with isoptionally mono-, di- or tri-substituted in the phenyl art by identicalor different substituents, substituents which may be mentioned being:halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with ineach case 1 to 4 carbon atoms, halogenoalkyl, halogenoalkoxy andhalogenoalkylthio with in each case 1 or 2 carbon atoms and 1 to 5identical or different halogen atoms, such as, preferably, fluorine andchlorine atoms, nitro- and cyano; and

R represents phenyl which is optionally mono-, di- or tri-substituted byidentical or different substituents, preferred substituents which may bementioned being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy andalkylthio with in each case 1 to 4 carbon atoms, halogenoalkyl,halogenoalkoxy and halogenoalkylthio with in each case 1 or 2 carbonatoms and 1 to 5 identical or different halogen atoms, such as,preferably, fluorine and chlorine atoms, nitro, cyano, hydroxyl,hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkylpart, hydroximinoalkyl with 1 to 4 carbon atoms, alkoximinoalkyl with 1to 4 carbon atoms in each alkyl part and phenyl, phenoxy, benzyl andbenzyloxy, each of which is optionally substituted by halogen and/oralkyl with 1 or 2 carbon atoms; or

R preferably represents the grouping ##STR29## wherein Alk¹ representsstraight-chain or branched alkyl with 1 to 4 carbon atoms; and

Alk² represents straight-chain or branched alkyl with 1 to 4 carbonatoms; or

Alk¹ and Alk², together with the carbon atom to which they are bonded,represent a 3-membered to 7-membered cycloaliphatic ring; and

R¹ represents straight-chain or branched alkyl with 1 to 6 carbon atoms,alkenyl with 2 to 4 carbon atoms, or phenyl, phenylalkyl with 1 to 4carbon atoms in the alkyl part, phenoxy, phenylthio, phenoxyalkyl with 1to 4 carbon atoms in the alkyl part, phenyl, thioalkyl with 1 to 4carbon atoms in the alkyl part, benzyloxy or benzylthio, each of whichis optionally mono-, di- or tri-substituted in the phenyl part byidentical or different substituents, preferred possible substituentsbeing the substituents on phenyl already mentioned for R.

Particularly preferred compounds of the formula (I) are those in which

A represents a nitrogen atom or the CH group,

B represents a nitrogen atom or the CH group,

X represents hydrogen or straight-chain or branched alkyl with 1 to 4carbon atoms,

Y represents straight-chain or branched alkyl with 1 to 4 carbon atoms;or, if X represents hydrogen, also allyl, methallyl, propargyl,methylpropargyl or benzyl which is optionally mono- or di-substituted inthe phenyl part by identical or different substituents, substituentswhich may be mentioned being: fluorine, chlorine, bromine, methyl,isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, nitro and cyano;

R represents phenyl which is optionally mono- or di-substituted byidentical or different substituents, substituents which may be mentionedbeing: fluorine, chlorine, bromine, methyl, isopropyl, tert.-butyl,methoxy, methylthio, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl,methoxycarbonyl, ethoxycarbonyl, hydroximinomethyl, 1-hydroximinoethyl,methoximinomethyl, 1-methoximinoethyl and phenyl, phenoxy, benzyl andbenzyloxy, each of which is optionally substituted by fluorine, chlorineor methyl; or

R represents the grouping ##STR30## wherein Alk¹ represents methyl orethyl; and

Alk² represents methyl or ethyl; or

Alk¹ and Alk², together with the carbon atom to which they are bonded,represent cyclobutyl, cyclopentyl or cylohexyl; and

R¹ represents methyl, ethyl, n-propyl, i-propyl, n-butyl, neopentyl, orphenyl, benzyl, phenethyl, phenoxy, phenylthio, phenoxymethyl,phenoxyethyl, phenylthiomethyl, phenylthioethyl, benzyloxy orbenzylthio, each of which is optionally mono- or di-substituted in thephenyl part by identical or different substituents, possiblesubstituents being the substituents on phenyl which have already beenmentioned for R.

Addition products of acids and those substituted diazolylalkyl-carbinolsof the formula (I) in which the substituents A, B, X, Y and R have themeanings which have already been mentioned as preferred for thesesubstituents are also preferred compounds according to the invention.

Preferred acids which can be added on azoles mentioned under a), b), c),d) and e) include hydrogen halide acids, such as, for example,hydrochloric acid and hydrobromic acid, in particular hydrochloric acid,and furthermore phosphoric acid, nitric acid, monofunctional andbifunctional carboxylic acids and hydroxycarboxylic acids, such as, forexample acetic acid, maleic acid, succinic acid, fumaric acid, tartaricacid, citric acid, salicyclic acid, sorbic acid and lactic acid, andsulphonic acids, such as o-toluenesulphonic acid and1,5-naphthalenedisulphonic acid.

b) Substituted 1,3-diazolyl-2-propanols of the general formula ##STR31##in which Alk¹ represents straight-chain or branched alkyl and

Alk² represents straight-chain or branched alkyl, or

Alk¹ and Alk² together represent a cycloaliphatic ring,

X represents a nitrogen atom or the CH group,

Y represents a nitrogen atom or the CH group and

R represents in each case optionally substituted phenyl, phenylalkyl,phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl, benzyloxy orbenzylthio,

and physiologically acceptable acid addition salts thereof.

The substituted 1,3-diazolyl-2-propanols of the formula (I') areobtained by a process in which 2-azolylmethyl-oxiranes of the formula##STR32## in which Alk¹, Alk², R and X have the abovementioned meaning,are reacted with azoles of the formula ##STR33## in which Y has theabovementioned meaning, in the presence of a diluent and, ifappropriate, in the presence of a base.

If appropriate, an acid can then be added onto the compounds of theformula (I') thus obtained.

Moreover, the compounds of the general formula (I') in which Rrepresents in each case optionally substituted phenylthio,phenylthioalkyl or benzylithio can be oxidised to the corresponding SOor SO₂ derivatives in the customary manner.

Formula (I') provides a general definition of substituted1,3-diazolyl-2-propanols according to this section b) of the invention.Preferably, in this formula,

Alk¹ represents straight-chain or branched alkyl with 1 to 4 carbonatoms; and

Alk² represents straight-chain or branched alkyl with 1 to 4 carbonatoms; or

Alk¹ and Alk² together represent a 3-membered to 7-memberedcycloaliphatic ring,

X represents a nitrogen atom or the CH group;

Y represents a nitrogen atom or the CH group; and R represents phenyl,phenylalkyl with 1 to 4 carbon atoms in the alkyl part, phenoxy,phenylthio, phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part,phenylthioalkyl with 1 to 4 carbon atoms in the alkyl part, benzyloxy orbenzylthio, each of which is optionally mono-, di- or tri-substituted inthe phenyl part by identical or different substituents, preferredsubstituents which may be mentioned being: halogen, alkyl with 1 to 4carbon atoms, alkoxy and alkylthio with in each case 1 to 4 carbonatoms, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in eachcase 1 or 2 carbon atoms and 1 to 5 identical or different halogenatoms, such as, preferably, fluorine and chlorine atoms, nitro, cyano,hydroxyl, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms inthe alkyl part, alkoximinoalkyl with 1 to 4 carbon atoms in each alkylpart, and phenyl, phenoxy, benzyl and benzyloxy, each of which isoptionally substituted by halogen and/or alkyl with 1 or 2 carbon atoms.

Particularly preferred compounds of the formula (I') are those in which

Alk¹ represents methyl or ethyl; and

Alk² represents methyl or ethyl; or

Alk¹ and Alk², together with the carbon atom to which they are bonded,represent cyclobutyl, cyclopentyl or cyclohexyl,

X represents a nitrogen atom or the CH group;

Y represents a nitrogen atom or the CH group; and

R represents phenyl, benzyl, phenethyl, phenoxy, phenylthio,phenoxymethyl, phenoxyethyl, phenylthiomethyl, phenylthioethyl,benzyloxy or benzylthio, each of which is optionally mono- ordisubstituted in the phenyl part by identical or different substituents,substituents which may be mentioned being: fluorine, chlorine, bromine,methyl, isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, nitro, cyano, hydroxyl,hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroximinoethyl,1-hydroximinoethyl, methoximinomethyl, 1-methoximinoethyl, and phenyl,phenoxy, benzyl and benzyloxy, each of which is optionally substitutedby fluorine, chlorine or methyl.

Addition products of acids and those substituted1,3-diazolyl-2-propanols of the formula (I') in which the substituentsAlk¹, Alk², X, Y and R have the meanings which have already beenmentioned as preferred for these substituents are also preferredcompounds according to the invention.

c) Substituted azolylcyclopropyl-azolylmethyl-carbinol derivatives ofthe formula (I") ##STR34## in which Ar represents optionally substitutedaryl or optionally substituted heteroaryl,

R represents hydrogen, alkyl, alkenyl, alkinyl, trialkylsilyl,optionally substituted phenylalkyl or the acyl radical,

X represents a nitrogen atom or the CH group, and

Y represents a nitrogen atom or the CH group,

and their acid addition salts have good anitimicrobial, in particularantimycotic, properties when used according to this invention.

The substituted azolylcyclopropyl-azolylmethylcarbinol derivatives ofthe formula (I") which are to be used according to the invention show agood spectrum of action in certain areas of indication.

The substituted azolylcyclopropyl-azolylmethylcarbinol derivatives aregenerally defined by formula (I"). In this formula,

Ar preferably represents phenyl which optionally has one or several,identical or different, substituents, the substituents which may bementioned as being preferred being: halogen; alkyl, alkoxy and alkylthioeach having 1 to 4 carbon atoms; halogenoalkyl, halogenoalkoxy andhalogenoalkylthio each having 1 to 2 carbon atoms and 1 to 5 identicalor different halogen atoms, such as fluorine and chlorine atoms; as wellas phenyl or phenoxy each of which is optionally substituted by alkylhaving 1 or 2 carbon atoms and/or halogen; and furthermore representsnaphthyl and a 5- to 6-membered heteroaromatic which optionally has oneor several identical or different, substituents and nitrogen, oxygenand/or sulphur as the heteroatoms, the suitable substituents which arepreferred being the abovementioned phenyl substituents;

R preferably represents hydrogen, straight-chain or branched alkylhaving 1 to 4 carbon atoms, straight-chain or branched alkenyl andalkinyl each having 2 to 4 carbon atoms, trialkylsilyl having 1 to 4carbon atoms in each alkyl moiety, alkylcarbonyl having 1 to 4 carbonatoms in the alkyl moiety, and represents phenylalkyl which optionallyhas one or several, identical or different, substituents, with 1 to 2carbon atoms in the alkyl moiety, the suitable substituents which arepreferring being the phenyl substituents already mentioned for Ar; and

X and Y represent the meanings given in the definition of the invention.

Particularly preferred compounds of the formula (I") are those in which

Ar represents phenyl which optionally has one to three, in particularone or two, identical or different substituents, the substituents whichmay be mentioned being: fluorine, chlorine, methyl, isopropyl,tert.-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, and phenyl or phenoxy each of which is optionallysubstituted by fluorine, chlorine and/or methyl; furthermore representsnaphthyl and represents furyl, thienyl, pyridinyl or pyrimidinyl, eachof which optionally has one or two, identical or different, substituentssuitable substituents being the abovementioned phenyl substituents;

R¹ represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, allyl, propargyl, trimethylsilyl, methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl, and represents benzyl which optionally has one tothree, in particular one or two, identical or different substituents,suitable substituents which are preferred being the phenyl substituentsalready mentioned for Ar; and

X and Y represent the meanings given in the definition of the invention.

Preferred compounds according to this section of the invention are alsoaddition products of acids and those substitutedazolylcyclopropyl-azolylmethylcarbinol derivatives of the formula (I")in which Ar, R, X and Y have the meanings which have already beenmentioned as preferred for these radicals.

d) substituted azolylmethyl-cyclopropyl-carbinol derivatives of theformula (I"') ##STR35## in which Ar represents optionally substitutedaryl or optionally substituted heteroaryl,

R¹ represents hydrogen, alkyl, alkenyl, alkinyl, trialkylsilyl,optionally substituted phenylalkyl or the acyl radical,

R² represents halogen, cyano, thiocyano, alkylcarbonyloxy,alkylcarbonylthio or the groups --X--R³ and --NR⁴ R⁵, as well ashydrogen when Ar represents optionally substituted heteroaryl,

R³ represents alkyl, cycloalkyl, alkenyl, alkinyl, hydroxyalkyl,carboxyalkyl, alkoxycarbonylalkyl, optionally substituted aryl,optionally substituted aralkyl, or the radical of the formula ##STR36##R⁴ and R⁵ are identical or different and represent hydrogen or alkyland, together with the nitrogen atom to which they are bonded, representan optionally substituted cycloaliphatic ring which optionally containsother heteroatoms,

X represents oxygen, sulphur, the SO or SO₂ group, and

Y represents a nitrogen atom or the CH group, and their acid additionsalts, have good antimycotic properties.

The substituted azolylmethyl-cyclopropyl-carbinol derivatives of theformula (I"') which are to be used according to this section ofinvention show a good spectrum of action in certain areas of indication.

The substituted azolylmethyl-cyclopropyl-carbinol derivatives accordingto the invention are generally defined by formula (I"'). In thisformula,

Ar preferably represents phenyl which optionally has one or several,identical or different, substituents, the substituents which may bementioned as being preferred being: halogen, alkyl, alkoxy and alkylthioeach having 1 to 4 carbon atoms; halogenoalkyl, halogenoalkoxy andhalogenoalkylthio each having 1 to 2 carbon atoms and 1 to 5 identicalor different halogen atoms, such as fluorine and chlorine atoms; as wellas phenyl or phenoxy each of which is optionally substituted by alkylhaving 1 or 2 carbon atoms and/or halogen; and furthermore representsnaphthyl and a 5- to 6-membered heteroaromatic which optionally has oneseveral, identical or different, substituents and nitrogen, oxygenand/or sulphur as the heteroatoms, the suitable substituents which arepreferred being the above mentioned phenyl substituents;

R¹ preferably represents hydrogen, straight-chain or branched alkylhaving 1 to 4 carbon atoms, straight-chain or branched alkenyl andalkinyl, each having 2 to 4 carbon atoms, trialkylsilyl having 1 to 4carbon atoms in each alkyl part, alkylcarbonyl having 1 to 4 carbonatoms in the alkyl part, and phenylalkyl which has one or two carbonatoms in the alkyl part and is optionally monosubstituted orpolysubstituted by identical or different substituents, preferredsubstituents being the phenyl substituents already mentioned for Ar,

R² preferably represents fluorine, chlorine, bromine, cyano, thiocyano,alkylcarbonyloxy having 1 to 4 carbon atoms in the alkyl part,alkylarbonylthio having 1 to 4 carbon atoms in the alkyl part, or thegroupings --X--R³ and --NR⁴ R⁵,

wherein

R³ preferably represents straight-chain or branched alkyl having 1 to 18carbon atoms, cycloalkyl having 3 to 8 carbon atoms, straight-chain orbranched alkenyl having 2 to 18 carbon atoms, straight-chain or branchedalkinyl having 2 to 18 carbon atoms, hydroxyalkyl having 1 to 18 carbonatoms, alkylthioalkyl having 1 to 6 carbon atoms in the alkylthio partand 1 to 6 carbon atoms in the alkyl part, carboxyalkyl having 1 to 18carbon atoms in the alkyl part, alkoxycarbonylalkyl having 1 to 6 carbonatoms in the alkoxy part and 1 to 6 carbon atoms in the alkyl part, andphenyl or phenylalkyl having 1 to 2 carbon atoms in the alkyl part, eachof which is optionally monosubstituted or polysubstituted by identicalor different substituents, preferred substitutents in each case beingthe phenyl substituents mentioned as being preferred for Ar, or

R³ represents the radical of the formula ##STR37## R⁴ and R⁵independently or one another preferably represent hydrogen orstraight-chain or branched alkyl having 1 to 4 carbon atoms, or

R⁴ and R⁵, together with the nitrogen atom to which they are bonded,preferably represent a 5-membered or 6-membered ring which is optionallysubstituted by alkyl having 1 to 4 carbon atoms or alkylcarbonyl having1 to 4 carbon atoms in the alkyl part, and can contain oxygen, sulphurand/or nitrogen as further heteroatoms, and

X preferably represents hydrogen when Ar represents an optionallysubstituted 5-membered or 6-membered heteroaromatic, and

Y preferably represents nitrogen or a CH group.

Particularly preferred compounds of the formula (I"') are those in which

Ar represents phenyl which is optionally monosubstituted ortrisubstituted, in particular monosubstituted or disubstituted, byidentical or different substituents, the following being mentioned assubstituents: fluorine, chlorine, methyl, isopropyl, tert.-butyl,methoxy, methylthio, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, and phenyl or phenoxy, each of which is optionallysubstituted by fluorine, chlorine and/or methyl; and furthermorerepresents naphthyl, and represents furyl, thienyl, pyridinyl orpyrimidinyl, each of which is optionally monosubstituted ordisubstituted by identical or different substituents, suitablesubstituents being the above mentioned phenyl substituents;

R² represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, allyl, propargyl, trimethylsilyl, methylcarbonyl,ethylcarbonyl, n-propyl-carbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl, and benzyl which is optionally monosubstituted ordisubstituted, in particular monosubstituted or disubstituted, byidentical or different substituents, preferred substituents being thephenyl substituents already mentioned as being preferred for Ar,

R² represents fluorine, chlorine, bromine, cyano, thiocyano,methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy,methylcarbonylthio, ethylcarbonylthio, n-propylcarbonylthio,isopropylcarbonylthio, n-butylcarbonylthio, isobutylcarbonylthio or thegroupings --X--R³ or --NR⁴ R⁵,

wherein

R³ represents straight-chain or branched alkyl having 1 to 12 carbonatoms, cycloalkyl having 5 to 7 carbon atoms, straight-chain or branchedalkenyl having 2 to 12 carbon atoms, straight-chain or branched alkinylhaving 2 to 12 carbon atoms, hydroxyalkyl having 1 to 12 carbon atoms,alkylthioalkyl having 1 to 4 carbon atoms in the alkylthio part and 1 to4 carbon atoms in the alkyl part; carboxyalkyl having 1 to 12 carbonatoms in the alkyl part, alkoxycarbonylalkyl having 1 to 4 carbon atomsin the alkoxy part and 1 to 4 carbon atoms in the alkyl part, and phenylor benzyl, each of which is optionally monosubstituted totrisubstituted, in particular monosubstituted to trisubstituted, inparticular monosubstituted or disubstituted, by identical or differentsubstituents already mentioned above for Ar as being particularlypreferred, or

R³ represents the radical of the formula ##STR38## R⁴ and R⁵independently of one another represent hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl or isobutyl, or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded,represent piperidinyl, piperazinyl or morpholinyl each of which isoptionally substituted by methyl, ethyl, methylcarbonyl orethylcarbonyl, and

X represents oxygen, sulphur, an SO group or an SO₂ group, andfurthermore

R² also represents hydrogen when Ar represents one of the abovementioned optionally substituted heteroaromatics, and

Y represents nitrogen or a CH group,

other preferred compounds according to the invention are additionproducts of acids and those substitutedazolylmethyl-cyclopropyl-carbinol derivatives of the formula (I"') inwhich Ar, R¹, R² and Y have the meanings which have already beenmentioned as being preferred for these radicals.

The substituted azolylmethyl-cyclopropyl-carbinol derivatives which areto be used according to this section of the invention and their acidaddition salts have not yet been described. They can be obtained in agenerally known manner.

e) Hydroxyethyl-azole derivatives of the general formula ##STR39## inwhich R¹ represents alkyl or the grouping Ar-Y-,

Ar represents optionally substituted aryl,

Y represents a direct bond or the groupings --CH₂ --, --CH₂ --CH₂ --,--OCH₂ --, --SCH₂ --, --CH═CH-- or --C.tbd.C--,

X represents a nitrogen atom or the CH group,

Z represents oxygen or the NOR² group and

R² represents hydrogen, alkyl, alkenyl, alkinyl, optionally substitutedaralkyl or optionally substituted cycloalkylalkyl,

and acid addition salts thereof, have good antimycotic properties forthe purpose of the present invention.

The compounds of the formula (I"") have an asymmetric carbon atom andcan therefore be obtained in the two optical isomer forms.

The hydroxyethyl-azole derivatives of the formula (I"") to be usedaccording to this section of the invention have a good action spectrumin certain fields of indication.

Formula (I"") provides a general definition of the hydroxyethyl-azolederivatives according to the invention. Preferably, in this formula

R¹ represents straight-chain or branched alkyl with 1 to 6 carbon atomsor the grouping Ar-Y;

Ar represents naphthyl, or phenyl which is optionally monosubstituted orpolysubstituted by identical or different substituents, preferredsubstituents which may be mentioned being: halogen, alkyl with 1 to 4carbon atoms, alkoxy and alkylthio with in each case 1 or 2 carbonatoms, nitro, halogenoalkyl, halogenoalkoxy and halogenoalkylthio within each case 1 or 2 carbon atoms and 1 to 5 identical or differenthalogen atoms, such as, preferably, fluorine and chlorine atoms, the--CH═NOR² radical, and phenyl, phenoxy, benzyl and benzyloxy, each ofwhich is optionally substituted by halogen and/or alkyl with 1 or 2carbon atoms;

X represents a nitrogen atom or the CH group;

Y represents a direct bond or the groupings --CH₂ --, --CH₂ CH₂ --,--OCH₂ --, --SCH₂ --, --CH═CH-- or --C.tbd.C--;

Z represents oxygen or the NOR² group; and

R² represents hydrogen, straight-chain or branched alkyl with 1 to 6carbon atoms, alkenyl or alkinyl with in each case 2 to 6 carbon atoms,or phenylalkyl which has 1 or 2 carbon atoms in the alkyl part and isoptionally monosubstituted or polysubstituted by identical or differentsubstituents, possible substituents on the phenyl being the substituentson phenyl which have already been mentioned in the case of Ar; orrepresents cycloalkylmethyl which has 5 or 6 carbon atoms in thecycloalkyl part and is optionally mono-, di-or trisubstituted byidentical or different alkyl radicals with 1 to 3 carbon atoms.

Particularly preferred compounds of the formula (I"") are those in which

R¹ represents straight-chain alkyl with 1 to 6 carbon atoms or thegrouping Ar-Y-;

Ar represents naphthyl, or represents phenyl which is optionally mono-,di- or trisubstituted by identical or different substituents,substituents which may be mentioned being: fluorine, chlorine, methyl,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,methoximinomethyl, ethoximinomethyl and allyloximinomethyl, and phenyl,phenoxy, benzyl and benzyloxy, each of which is optionally substitutedby chlorine and/or methyl;

X represents a nitrogen atom or the CH group;

Y represents a direct bond or the groupings --CH₂ --, --CH₂ CH₂ --,--OCH₂ --, --SCH₂ --, --CH═CH-- or --C.tbd.C--; and

Z represents oxygen or the NOR² group,

wherein

R² represents hydrogen, methyl, ethyl, n-propyl, n-butyl, allyl orpropargyl, or represents benzyl which is optionally mono-, di- ortrisubstituted by identical or different substituents from the groupcomprising fluorine, chlorine, methyl, trifluoromethyl andtrifluoromethoxy, or represents cyclohexylmethyl which is optionallysubstituted by methyl or ethyl.

Another preferred embodiment of the invention are compositionscomprising a fungicidally effective amount of a nikkomycin derivativeselected from the group consisting of nikkomycins Z_(t), X_(t), B, Bx, Cand Cx (see U.S. Pat. No. 4,585,761, U.S. Pat. No. 4,315,922, U.S. Pat.No. 4,158,608 and U.S. Pat. No. 4,046,881) and an antimycotically activeand optionally orally applicable azole.

Moreover, antimycotic compositions are preferred comprising an azoleantimycotic selected from the group consisting of ketoconazole,itraconazole, fluconazole, clotrimazole, miconazole, bifonazole,1-(4-chlorphenyl) -2-methyl-2-methoximo-methyl-1-(1,2,4-triazol-1-yl-methyl)-1-propanol,1-(4-chlorphenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-2-butanoland 4-(fluorphenyl) -(1-methylsulfinyl-1-cyclopropyl)-(1,2,4-triazol-1-yl-methyl)-methanol.

The antimycotic compositions according to the invention contain afungicidally effective amount of a nikkomycin derivative and an azoleantimycotic in a ratio of 1:1 to 30:1, preferably 3:1 to 10:1.

Preferred are also antimycotic compositions according to the inventioncomprising a fungicidally effective amount of a nikkomycin derivativeand an azole antimycotic selected from the group consisting ofketoconazole, itraconazole, fluconazole, clotrimazole, miconazole,bifonazole,1-(4-chlorphenyl)-2-methyl-2-methoximo-methyl-1-(1,2,4-triazol-1-yl-methyl-1-propanol,1-(4-chlorphenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-2-butanoland 4-(fluorphenyl)-(1-methylsulfinyl-1-cyclopropyl)-(1,2,4-triazol-1-yl-methyl)-methanol and, moreover, the antimycotic compositions comprisinga fungicidally effective amount of nikkomycin Z and1(4-chlorphenyl)-2-methyl-2-methoximomethyl1-(1,2,3-triazol-1-yl-methyl-1-propanol,1-(4-chlorphenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl) -2-butanoland/or4-(fluorphenyl)-(1-methylsulfinyl-1-cyclopropyl)-(1,2,4-triazol-1-yl-methyl)-methanol.

A further embodiment of the invention are nikkomycins in combinationwith antimycotically active and optionally orally applicable azoles foruse in a method for therapeutical treatment of the human or animal bodyinfected with fungi.

The invention is also related to the use of nikkomycin derivatives incombination with antimycotically active and optionally orally applicableazoles for the preparation of antimycotically active pharmaceuticalcompositions and to a process for the preparation of antimycoticallyactive pharmaceutical compositions comprising mixing a combination of afungicidally effective amount of a nikkomycin derivative and an azolederivative with a solid or liquid diluent and/or carrier or otherauxiliaries useful for the preparation of pharmaceutical compositions,said nikkomycin derivative and azole derivative preferably being presentin a ratio of 1:1 to 30:1.

Finally, the invention is also related to a method of treating human ornon-human animals infected with fungi, the method comprisingadministering to the human or non-human animal therapeutically effectiveamounts of a nikkomycin derivative and an azole antimycotic.

More specifically the invention is related to a method comprisingadministering to the human or non-human animal of from 1 mg/kg to 1,000mg/kg, preferably 10 mg/kg to 100 mg/kg of body weight per day of anikkomycin derivative and an azole antimycotic of the above identifiedtype. The method comprising administering the nikkomycin and the azolein a ratio of 1:1 to 30:1 is also preferred.

Preferably the compositions according to the invention are orallyadministered, but may be administered parenterally or via the inhalationof an aerosilized preparation.

EXPERIMENTAL PART FOR NIKKOMYCIN DERIVATIVES AND ANALOGUES N-alkylationof nikkomycin Z with aldehydes and ketones (Table 1, General Procedure

10 mmol of nikkomycin Z are dissolved in 100 ml of an H₂ O/methanolmixture and 50-100 mmol of the aldehyde or ketone dissolved in 20 ml ofmethanol are added. After stirring for 30 min. 10-15 mmol of NaBH₃ CNare added to the reaction mixture.

The mixture is stirred overnight (TLC control) until the reaction iscomplete. The excess NaBH₃ CN is eliminated by adding glacial aceticacid. The mixture is concentrated to dryness by evaporation andtriturated with ether. The powdery product is chromatographed on LH-20(ethanol/H₂ O=1:1). In many cases the mono- and dialkylation productsare produced concomitantly in the reaction with aldehydes. They areseparated from each other by chromatography.

N-Alkylation of nikkomycin Z with α-amino aldehydes (Table 2)

The procedure is analogous to the N-alkylation of nikkomycin C_(Z) withα-amino aldehydes (Table 6).

10 mmol of nikkomycin Z and 10 mmol of N-BOC-D/L-α-aminooctanal aredissolved (partly suspended) in 150 ml of methanol and 15 mmol of NaBH₃CN are added. By adding acetic acid the pH value is adjusted to pH 6-7.

The solution is filtered free of unreacted nikkomycin Z, concentrated byevaporating and chromatographed on LH-20 (ethanol/H₂ O=1:1).

The BOC protecting group is cleaved off in 30 ml of TFA/CH₂ Cl₂ (1:1) at0° C. over a period of 2 hours. The product is chromatographed onceagain on LH-20 (H₂ O/acetol=99.9:0.1). Yield after chromatography: 33%.

N-acylation of nikkomycin Z with α-amino acid reactive esters (Table 3,example) L-phenylalanine-nikkomycin Z

10 mmol of nikkomycin Z (=4.95 g) are dissolved in 50 ml of a DMF/H₂ Omixture and 1.38 ml of triethylamine are added while cooling with ice(protection of the carboxyl group by a salt).

Then 11 mmol (=6.26 g) of N-BOC-L-phenylalanine-ONP-ester in 5 ml of DMFand 1.38 g of hydroxybenztriazole are added. TLC control on celluloseusing n-propanol/H₂ O/acetic acid=60:40:0.5 or 80:20:0.5.

The mixture is stirred overnight. After the reaction is complete theDMF/H₂ O mixture is stripped off under a high vacuum and the sample isdried (under a high vacuum). It is taken up in water and extracted firstwith ether and then with ethyl acetate in order to substantially removeresidual DMF, hydroxyenztriazole and nitrophenol (pH kept at between6-7). Then the aqueous phase is concentrated by evaporation and driedunder a high vacuum.

To cleave the BOC protecting group from the tripeptide the product isdissolved in CH₂ Cl₂ /TFA=1:1 while cooling with ice and the solution isallowed to reach room temperature (TLC control). When the cleavage iscomplete the mixture is concentrated by evaporation, the remaining TFAis removed azeotropically with toluene and the product is dried under ahigh vacuum.

The product is chromatographed on LH-20 with ethanol/H₂ O/ethanol/H₂O/acetic acid=50:50:0.1 (twice). 1.65 g of a ¹ H-NMR-pure ripeptide areobtained (yield: 25.7%).

Identification: ¹ H-NMR.

N-acylation of nikkomycin Z with reactive esters (Table 4, example)

The procedure is similar to the N-acylation of nikkomycin Z with α-aminoacid reactive esters.

10 mmol of nikkomycin Z are dissolved in 50 ml of a DMF/H₂ O mixture and1.38 ml of triethylamine are added while cooling with ice. Then 11 mmolof palmitic acid ONP ester and 1.38 g of hydroxybenztriazole are added.The yield following chromatography on LH-20 (mobile solvent: ethanol) is41%.

N-acylation of nikkomycin C_(Z) with α-amino acid reactive esters (Table5, example) p-Methoxy-D/L phenylglycine C_(Z)

10 mmol of nikkomycin C_(Z) (2.87 g) are dissolved in 20 ml of a DMF/H₂O mixture and 1.38 mol of triethylamine are added while cooling with ice(protection of the carbonyl group by a salt). Then 10 mmol (4.02 g) ofN-BOC-D/L-phenylglycine ONP ester in 5 mol of DMF and 1.35 g ofhydroxybenztriazole are added.

Partially precipitated components dissolve on stirring the mixtureovernight.

TLC control on cellulose using n-propanol/H₂ O/acetic acid=60:40:0.5 or80:20:0.5.

When the reaction is complete (pH kept at between 6-7) the DMF/H₂ Omixture is stripped off and the sample dried under a high vacuum. Theproduct is worked up and TFA cleaved off following the same procedure asfor the N-acylation of Nikkomycin Z with α-amino acid reactive esters.

The product is chromatographed on LH-20 using ethanol/H₂ O/aceticacid=50:50:0.1.

    ______________________________________                                        Yield: Fractions 72-85    1.1 g (slightly contaminated)                                        86-105   2.5 g                                                                = 79%    total yield,                                        ______________________________________                                    

Identification: ¹ H-NMR

N-Alkylation of Nikkomycin C₂ -with α-aminoaldehydes (Table 6, example)N-BOC-homo phenylalaninal

2.93 g of N-BOC homo phenylalanine methyl ester (10 mmol) are dissolvedin 25 ml of absolute toluene under nitrogen and the solution is cooledto -80° C. 20 ml of ˜20% strength DIBA in toluene are added dropwise andthe temperature maintained. Since the reaction was not complete after1.5 h a further 3 ml of 20% strength DIBA were added.

Working up

After 1 ml of methanol has been added the reaction mixture is added to10 ml of a saturated potassium sodium tartrate solution of 60 ml of H₂ O(0° C.). After stirring a gelatinous precipitate forms. It is filteredoff and washed with ether. The product is extracted from the aqueousphase quantitatively, using ether. The combined ether and toluene phasesare dried over Na₂ SO₄ and concentrated by evaporation. An oil isobtained which is separated by means of a small silica gel column usingpentane/ethyl acetate (85/15).

Yield: 60.8%.

    ______________________________________                                        TLC/silica gel: Rf = 0.78 (ester)                                                             Rf = 0.68 (aldehyde)                                                          CHCl.sub.3 /methanol (9/1);                                                   spray reagent: DNP/ethanol                                    ______________________________________                                    

Identification: ¹ H-NMR (ppm) 9.42 (1H, CHO); 7.25 (5H, m, Aryl); 5.2(1H,br, BOCNH); 4.18 (1H,br.m, NH--CH--CHO); 2.7 (2H,br.m, --CH₂ --);2.0 (2H,br.m, --CH₂ --); 1.43 (9H, s, (CH₃)₃ --C)

Coupling of nikkomycin C_(Z) with N-BOC-homo phenylalaninal

2 g of nikkomycin C_(Z) (7 mmol) are dissolved in 70 ml of methanol atroom temperature and 2.2 g of N-BOC-homo phenylalaninal in 30 ml ofmethanol are added dropwise. After stirring for 15 min. 441 mg of NaBH₃CN are added. After stirring overnight the reaction was complete (TLCcontrol). The excess NaBH₃ CN is decomposed with acetic acid. Afterconcentrating the mixture by evaporation the residue is triturated withether.

After cleaving off the BOC group with CH₂ Cl₂ /TFA at 0° C.→RT (TLCcontrol) the product is chromatographed on Sephadex LH-20 usingethanol/H₂ O/acetic acid (50/50/0.1). The coupling product is obtainedin an 80% yield.

TLC/silica gel: propanol/H₂ O/acetic acid (80/20/0.5).

Identification: ¹ H-NMR

                  TABLE 1                                                         ______________________________________                                        .sup.1 H shifts of the diastereomer mixture in D.sub.2 O                      H-atoms  (ppm)         H-atoms   (ppm)                                        ______________________________________                                        aromat. H                                                                              7.16-7.34      2H on C-1                                                                              3.318                                        -olef.H  7.606;7.598   1H on C-2 3.598                                                                         (broadened)                                  -olef.H  5.823;5.813   2H on C-3 2.015                                        H on C-1'                                                                              5.756 (broadened)                                                                           2H on C-4 2.723                                        H on C-2'                                                                              4.266;4.251                                                          H on C-3'                                                                              4.523;4.498                                                          H on C-4'                                                                              3.965;3.911                                                          H on C-5'                                                                              4.330;4.311                                                          ______________________________________                                    

The synthesis in the case where R=CH₂ phenyl was carried out by the sameprocedure.

N-alkylation of nikkomycin C_(Z) with aldehydes (Table 7, example)

The N-alkylation of nikkomycin C_(Z) is similar to the N-alkylation ofnikkomycin Z with α-amino aldehydes.

10 mmol of nikkomycin C_(Z) are dissolved in 200 mol of an H₂ O/methanolmixture and 20 mmol of phosphonoaldehyde disodium salt (Mw: 157) areadded. After stirring the mixture for 30 min. 1 g of NaBH₃ CN is added.The pH value of the reaction mixture is kept at pH 5-6 using aceticacid.

The mixture is stirred overnight (TLC control). When the reaction iscomplete the excess NaBH₃ CN is eliminated by adding glacial aceticacid. The mixture is concentrated to dryness by evaporation. The powderyproduct is chromatographed on LH-20 (ethanol/H₂ O=1:1).

Yield: 77% (monoalkylation product).

Reduction of nikkomycin X to nikkomycin X alcohol (Table 8)

100 mmol of nikkomycin X are dissolved in 30 ml of acetic acid/H₂ O(1:1). The solution is hydrogenated (6 hours, RT, 3 bar) with 1 g offreshly reduced PO₂ and worked up. It is then chromatographed on LH-20with water and 0.1% acetic acid.

Yield after chromatography: 45%.

Nikkomycin derivatives according to the invention are specified in thefollowing tables:

                                      TABLE 1                                     __________________________________________________________________________    N-Alkylation of nikkomycin Z with aldehydes and ketons                         ##STR40##                                                                    R.sub.1        R.sub.2        Physical Data                                   __________________________________________________________________________    CH.sub.3       H              Confirmed by                                                                  .sup.1 H-NMR data                               CH.sub.3       CH.sub.3                                                       C.sub.2 H.sub.5                                                                              C.sub.2 H.sub.5                                                C.sub.3 H.sub.7                                                                              C.sub.3 H.sub.7                                                 ##STR41##     H                                                              C.sub.4 H.sub.9                                                                              C.sub.4 H.sub.9                                                 ##STR42##     H                                                               ##STR43##     H                                                               ##STR44##     H              Confirmed by NMR data                            ##STR45##     H                                                              (CH.sub.2).sub.6CH.sub.3                                                                     H                                                               ##STR46##     H                                                               ##STR47##     H                                                              CH.sub.2CHCH.sub.2                                                                           H                                                              CH.sub.2CHCHCH.sub.3                                                                         H                                                               ##STR48##     H                                                               ##STR49##                                                                                    ##STR50##                                                     (CH.sub.2).sub.11NH.sub.2                                                                    H                                                               ##STR51##     H              Confirmed by NMR data                            ##STR52##     H                                                               ##STR53##     H                                                               ##STR54##                                                                                    ##STR55##                                                      ##STR56##                                                                                    ##STR57##                                                      ##STR58##     H                                                               ##STR59##                                                                                    ##STR60##                                                      ##STR61##     H              Confirmed by NMR data                            ##STR62##                                                                                    ##STR63##                                                     __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        N-Alkylation of nikkomycin Z with α -amino aldehydes                     ##STR64##                                                                                     Configuration                                                R.sub.z .sub.-   of α-NH.sub.2                                                                       Physical Data                                    ______________________________________                                        H                M           Confirmed by                                                                  .sup.1 H-NMR data                                CH.sub.3         L                                                             ##STR65##       D/L                                                          C.sub.6 H.sub.13 D/L                                                          (CH.sub.2).sub.4NH.sub.2                                                                       L                                                             ##STR66##       D/L                                                           ##STR67##       D/L                                                          ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        N-Acylation of nikkomycin Z with α -amino acid reactive esters           ##STR68##                                                                                     Configuration                                                R.sub.z .sub.-   of α-NH.sub.2                                                                       Physical Data                                    ______________________________________                                        H                M           Confirmed by                                                                  .sup.1 H-NMR data                                CH.sub.3         L                                                             ##STR69##       L                                                             ##STR70##       L                                                             ##STR71##       L                                                            CH.sub.2CH.sub.2SCH.sub.3                                                                      L                                                            CH.sub.2 COOH    L                                                             ##STR72##       L           Confirmed by NMR data                            (CH.sub.2).sub.3NH.sub.2                                                                       L                                                            (CH.sub.2).sub.4NH.sub.2                                                                       L                                                            (CH.sub.2).sub.4NH.sub.2 xCF.sub.3 COOH                                                        L                                                             ##STR73##       L                                                             ##STR74##       L                                                             ##STR75##       D/L                                                           ##STR76##       D/L                                                           ##STR77##       L                                                            ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        N-Acylderivatives of nikkomycin Z with reactive esters                         ##STR78##                                                                    R.sub.z               Physical Data                                           ______________________________________                                        (CH.sub.2).sub.14CH.sub.3                                                                           Confirmed by                                                                  .sup.1 H-NMR data                                       (CHCH).sub.2CH.sub.3                                                          (CH.sub.2).sub.10NH.sub.2                                                     ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    N-Acylation of nikkomycin C.sub.Z with α-amino                          acid reactive esters                                                           ##STR79##                                                                                           Configuration                                          R.sub.z                of α-NH.sub.2                                                                   Physical Data                                  __________________________________________________________________________    CH.sub.2CH.sub.2CH.sub.3                                                                             D       Confirmed by                                                                  .sup.1 H-NMR data                              CH.sub.2CH.sub.2SCH.sub.3                                                                            L                                                      (CH.sub.2).sub.3CH.sub.3                                                                             D                                                       ##STR80##             D/L                                                     ##STR81##             D/L                                                     ##STR82##             D/L                                                     ##STR83##             D/L                                                     ##STR84##             D/L     Confirmed by NMR data                           ##STR85##             D/L                                                     ##STR86##             D                                                       ##STR87##             D/L                                                     ##STR88##             D                                                       ##STR89##             L                                                       ##STR90##             D/L     Confirmed by .sup.1 H-NMR data                  ##STR91##             L                                                       ##STR92##             D                                                       ##STR93##             L                                                       ##STR94##             D/L                                                     ##STR95##             D/L                                                    additionally:                                                                  ##STR96##                                                                                            ##STR97##                                             __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    N-Alkylation of nikkomycin C.sub.Z with α-amino-                        aldehydes                                                                      ##STR98##                                                                                          Configuration                                           R.sub.z               of α-NH.sub.2                                                                   Physical Data                                   __________________________________________________________________________    C.sub.6 H.sub.13      D/L     Confirmed by                                                                  .sup.1 H-NMR data                               CH.sub.3SCH.sub.2CH.sub.2                                                                           L                                                        ##STR99##            D/L                                                      ##STR100##           D/L                                                      ##STR101##           D/L                                                      ##STR102##           D/L                                                      ##STR103##           D/L     Confirmed by NMR data                            ##STR104##           D/L                                                      ##STR105##           L                                                        ##STR106##           D/L     Confirmed by NMR data                            ##STR107##           D/L                                                     (R,R-configuration)                                                            ##STR108##           D/L                                                      ##STR109##                                                                   __________________________________________________________________________     .sup.x) mixtures of diastereoisomers                                     

                  TABLE 7                                                         ______________________________________                                        N-Alkylation of nikkomycin C.sub.Z                                             ##STR110##                                                                   R.sub.z               Physical Data                                           ______________________________________                                        CH.sub.2(CH.sub.2).sub.10NH.sub.2                                                                   Confirmed by                                                                  .sup.1 H-NMR data                                        ##STR111##                                                                    ##STR112##                                                                   ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        Derivatives with substitution in the nucleoside                               portion                                                                        ##STR113##                                                                   R                      Physical Data                                          ______________________________________                                        Nikkomycin Z           Confirmed by                                                                  .sup.1 H-NMR data                                       ##STR114##                                                                   Nikkomycin X                                                                   ##STR115##                                                                    ##STR116##                                                                    ##STR117##                                                                   ______________________________________                                    

The compositions according to the invention can be used according to theinvention and display antimicrobial actions, in particular powerfulantimycotic actions. They possess a very broad antimycotic actionspectrum, especially against dermatophytes and yeasts

as well as biphasic fungi, for example against varieties of Candida,such as Candida albicans, varieties of Epidermophyton, such asEpidermophyton floccosum, varieties of Aspergillus, such as Aspergillusniger and Aspergillus fumigatus, varieties of Trichophyton, such asTrichophyton mentagrophytes, varieties of Microsporon, such asMicrosporon felineum and varieties of Torulopsis, such as Torulopsisglabrata. The listing of these micro-organisms in no way implies alimitation of the germs which can be combated but is only ofillustrative character. Such fungi include also Coccidioides immitis,Histoplasma capsulatum, Blastomyces dermatitidis and Paracoccidioidesbrasiliensis.

Examples which may be mentioned of fields of indication in humanmedicine are: dermatomycoses and systemic mycoses caused by Trichophytonmentagrophytes and other varieties of Trichophyton, varieties ofMicrosporon, Epidermophyton floccosum, yeasts and biphasic fungi as wellas moulds and varieties of Candida.

Examples which may be mentioned of field of indication in veterinarymedicine are: all dermatomycoses and systemic mycoses, especially thosecaused by the abovementioned pathogens.

The present invention includes pharmaceutical formulations which, inaddition to non-toxic, inert pharmaceutically suitable excipients,contain one or more active compounds according to the invention, orwhich consist of one or more active compounds according to theinvention, as well as processes for the preparation of theseformulations.

The present invention also includes pharmaceutical formulations indosage units. This means that the formulations are in the form ofindividual parts, for example tablets, dragees, capsules, pills,suppositories and ampoules, of which the content of active compoundcorresponds to a fraction or a multiple of an individual dose. Thedosage units can contain, for example, 1, 2, 3 or 4 individual doses or1/2, 1/3 or 1/4 of an individual dose. An individual dose preferablycontains the amount of active compound which is given in oneadministration and which usually corresponds to a whole, a half, a thirdor a quarter of a daily dose.

By non-toxic, inert pharmaceutically suitable excipients there are to beunderstood solid, semi-solid or liquid diluents, fillers and formulationauxiliaries of every kind.

Tablets, dragees, capsules, pills, granules, suppositories, solutions,suspensions and emulsions, pastes, ointments, gels, creams lotions,powders and sprays may be mentioned as preferred pharmaceuticalformulations.

Tablets, dragees, capsules, pills and granules can contain the activecompound or compounds alongside the customary excipients, such as (a)fillers and extenders, for example starches, lactose, sucrose, glucose,mannitol and silica, (b) binders, for example carboxymethylcellulose,alginates, gelatine and polvinylpyrrolidone, (c) humectants, for exampleglycerol, (d) disintegrating agents, for example agar-agar, calciumcarbonate and sodium bicarbonate, (d) solution retarders, for exampleparaffin, and (f) resorption accelerators, for example cetyl alcohol andglycerol monostearate, (h) adsorbents, for example kaolin and bentonite,and (i) lubricants, for example talc, calcium stearate and magnesiumstearate and solid polyethylene glycols, or mixtures of the substanceslisted under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided withthe customary coatings and shells, optionally containing opacifyingagents, and can also be of such composition that they release the activecompound or compounds only, or preferentially, in a certain part of theintestinal tracts, optionally in a delayed manner, examples of embeddingcompositions which can be used being polymeric substances and waxes.

The active compound or compounds, optionally together with one or moreof the abovementioned excipients can also be in a micro-encapsulatedform.

Suppositories can contain, in addition to the active compound orcompounds, the customary water-soluble or water-soluble excipients, forexample polyethylene glycols, fats, for example cacao fat, an higheresters (for example C₁₄ -alcohol with C₁₆ -fatty acid), or mixtures ofthese substances.

Ointments, pastes, creams and gels can contain, in addition to theactive compound or compounds, the customary excipients, for exampleanimal and vegetable fats, waxes, paraffins, starches, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silica, talc and zinc oxide, or mixtures of these substances.

Powders and sprays can contain, in addition to the active compound orcompounds, the customary excipients, for example lactose, talc, silica,aluminium hydroxide, calcium silicate and polyamide powders or mixturesof these substances. Sprays can additionally contain the customarypropellants, for example chlorofluorohydrocarbons.

Solutions and emulsions can contain, in addition to the active compoundor compounds, the customary excipients, such as solvents, solubilisingagents and emulsifiers, for example water, ethyl, alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,oils, especially cottonseed oil, groundnut oil, maize germ oil, oliveoil, castor oil and sesame oil, glycerol-formal, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitane, ormixtures of these substances.

For parenteral administration, the solutions and emulsions can also bein a sterile form which is isotonic with blood.

Suspensions can contain, in addition to the active compound orcompounds, the customary excipients, such as liquid diluents, forexample water, ethyl alcohol or propylene glycol, suspending agents, forexample ethoxylated isostearyl alcohols, polyoxyethylene sorbitol estersand sorbitane esters, micro-crystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances.

The formulation forms mentioned can also contain colorants,preservatives and additives which improve the odour and flavour, forexample peppermint oil and eucalyptus oil, and sweeteners, for examplesaccharin.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical formulations in a concentration of about0.1 to 99.5, preferably of about 0.5 to 95%, by weight of the totalmixture.

The abovementioned pharmaceutical formulations can also contain otherpharmaceutical active compounds in addition to the active compoundsaccording to the invention.

The abovementioned pharmaceutical formulations are prepared in thecustomary manner according to known methods, for example by mixing theactive compound or compounds with the excipient or excipients.

The present invention also includes the use of the active compoundsaccording to the invention, and of pharmaceutical formulations whichcontain one or more active compounds according to the invention, inhuman and veterinary medicine, for the prevention, alleviation and/orcure of the abovementioned diseases.

The active compounds or the pharmaceutical formulations can beadministered locally, orally, parenterally, intraperitoneally and/orrectally, preferably parenterally, and in particular intravenously, andaerosilized.

In general, it has proved advantageous both in human medicine and inveterinary medicine, to administer the active compound or compoundsaccording to the invention in total amounts of about 10 to 300,preferably 50 to 200, mg/kg of body weight every 24 hours, optionally inthe form of several individual administrations, in order to achieve thedesired results.

However, it can be necessary to deviate from the dosages mentioned, andin particular to do so as a function of the species and the body weightof the subject to be treated, the nature and severity of the disease,the nature of the formulation and of the administration of themedicament and the time or interval over which the administration takesplace. Thus it can in some cases suffice to manage with less than theabovementioned amount of active compound, whilst in other cases theabovementioned amount of active compound must be exceeded. Theparticular optimum required and the type of administration of the activecompounds can easily be determined by anyone skilled in the art on thebasis of his expert knowledge.

The following formulae show compounds according to the invention. TheFIGURES in parenthesis stand for their efficacy in C. albicans infectedmice. CFW-1 mice were infected intraveneously with 6×10⁵ cfu of Candidaalbicans. 100 mg/kg of active substance were administered orally 2 timesdaily during 3 days starting with the day of infection. Data weredetermined after 12 to 14 days when 80-90% of the control animals weredead.

Efficacy is defined as follows: 2 means that compound show activity. 3means good activity and 4 represents very good efficacy. ##STR118##

To test the ability of nikkomycin derivatives and azoles to actsynergistically, checkerboard in vitro assay was performed using theyeast Candida albicans.

Materials and Methods

Candida albicans strain B311 was grown overnight in glucose-yeastextract broth, washed, and adjusted to the desired density.

The tests were performed in 96-well microtiter plates using yeastnitrogen broth with dextrose and asparagine as the growth medium. Thetest materials were dissolved, diluted serially, then transferred to theappropriate wells of the microtiter plates so that the finalconcentrations ranged from 0.02-1 millimolar for the nikkomycins, and0.06-64 micrograms for the azoles. All wells were inoculated with 10,000organisms per milliliter (final concentration) and the plates incubatedat 30° C. for 48 hours. The plates were then examined and the degree ofgrowth for each well noted. Endpoints were determined for each row asbeing the lowest concentration showing the complete inhibition ofgrowth. Data were plotted as isobolograms showing the endpoints for thesingle compounds, as well as the endpoints for the various combinations.

Results

The data for the assays are presented in FIGS. 1-4. As can be seen, forthe azole R3783, the addition of nikkomycin derivatives results in adramatic lowering of the endpoints in comparison to the endpoints forthe single agents. As an example, FIG. 1 shows the endpoints for R3783alone to be 64 micrograms/milliliter and 1.0 millimolar for thenikkomycins. Surprisingly, with the concentrations of the combinationsemployed for this example, no growth was detected in the wellscontaining at least 0.125 mM nikkomycin R 5124 and 0.125 μg/ml of theazole R3783. Thus, the endpoint for the combination was reduced aminimum of 600-fold with respect to the azole endpoint, clear evidenceof synergy for these two classes of drugs.

We claim:
 1. A nikkomycin derivative selected from the group consistingof ##STR119##
 2. A method of treating an animal infected with fungi, themethod comprising administering to the animal an effective amount of anikkomycin derivative selected from the group consisting of ##STR120##